NEW YORK – Epigenetics company Volition sees a path toward expansion into East Asian markets, beginning with Taiwan, following the publication of a prospective study and ahead of a follow-up validation study of the ability of its Nu.Q lung cancer test to improve the specificity of low-dose computed tomography (LDCT) testing in identifying malignant lung nodules.
The Henderson, Nevada-based multinational firm also hopes to begin commercializing its lung cancer test in France in the coming months and to publish data on an ovarian cancer assay and a new sepsis assay next year.
The lung cancer study and its validation study are being conducted in collaboration with the National Taiwan University College of Medicine. The recently completed study is currently available as a preprint on MedRxiv and is undergoing peer review with the Annals of Surgical Oncology.
Louise Batchelor, chief marketing and communications officer at Volition, explained that there is currently no regulator-approved and widely adopted blood test for the early detection of lung cancer. While LDCT is a standard method for detecting and monitoring lung nodules, it has a high false positive rate, leading in many cases to unnecessary testing, anxiety, and higher medical costs for patients.
"LDCT is very sensitive, but it's not very specific," Batchelor said.
In their study, investigators collected blood from 755 adults with a nodule greater than 5 mm detected by LDCT and biopsied to confirm malignancy in the case of non-small cell lung cancer. That cutoff for nodule size was chosen because guidelines for Asia recommend that nodules with a diameter of 5 mm or greater undergo clinical management. Volition's Nu.Q assays were used to quantify the amount of circulating nucleosomes carrying certain histone modifications, and these were used in turn to develop an epigenetic biomarker (EB) model for calculating the risk of malignancy in lung nodules and to more accurately classify those nodules.
Nu.Q, which stands for nucleosome quantification, consists of extracting and analyzing free nucleosomes, segments of DNA wound around histones that can be found at elevated levels in the blood of cancer patients, via an ELISA assay targeting histone H3.1.
Samples were split into training, validation, and test datasets, and the epigenetic biomarker model was trained on 483 samples, validated on 121 samples, and independently tested on 202 samples. The researchers began building the model with five histone modifications and found that only two –– H3.1 and H3K27me3 –– were the most informative.
Low levels of H3K27me3 in tissues have been associated with lung cancer development, whereas a high level of circulating H3K27Me3-bearing nucleosomes has been associated with lung cancer at diagnosis and during treatment.
"H3K27me3 is definitely the marker of choice in lung cancer," Batchelor said.
In addition to lung cancer, H3K27me3 overexpression is also linked to a more malignant behavior and worse prognosis in patients with prostate, esophageal, nasopharyngeal, and hepatocellular carcinoma. Conversely, in breast, ovarian, and pancreatic cancers, and in renal cell carcinoma, reduced H3K27me3 expression is associated with a worse prognosis.
The EB model showed strong performance measures across datasets, including in the smaller nodules that are often the source of false positives by LDCT.
The EB model also performed well in different nodule types, such as solid, part-solid, and ground-glass opacity nodules, indicating a potential future utility in assessing pulmonary nodules.
Christopher Mueller, a professor of cancer biology and genetics at Canada's Queen's University who is not involved with the research, said via email that despite deriving a simple model with very reasonable performance metrics, the study was generally underpowered for benign patients and did not have a large enough control population to adequately address some of the performance issues.
"In particular," he wrote, "the false negative rates were very high and speak to the overall lower level of specificity, which is very important for what would be a complementary screening assay."
Having an easy-to-implement supplemental assay that could improve the overall diagnostic accuracy of tests such as LDCT would be of benefit in both targeted and population-based screening programs, Mueller wrote. The simplicity of Nu.Q, he added, might fall short of the insights that one could gain from other methods under development, such as fragmentomics, a liquid biopsy technique that analyzes the size, amount, and pattern of circulating DNA fragments.
"Overall, I doubt that looking at bulk levels of nucleosome-associated posttranslational modifications will be able to provide the needed insight into disease development," Mueller said. "That being said, if something this simple was feasible, it would be much more easily implemented than assays which require high levels of sequencing and sophisticated analysis."
Volition and its collaborators are currently preparing to launch a 500-participant validation study to gather data needed to support Nu.Q's possible inclusion into Taiwan's national lung cancer screening program. Batchelor said that Taiwan is an ideal location for this study because it's one of a few countries with such a program.
Volition is also eyeing Taiwan as a potential steppingstone into the Chinese market.
"From an ethnicity point of view," Batchelor said, "Taiwan is very similar to China. That could potentially give us access to the Chinese market without necessarily having to do big studies in China."
Batchelor said that researchers affiliated with Japan's national cancer screening programs have also expressed interest in studying Volition's assays for possible inclusion, although no deals have yet been signed.
The company is also currently evaluating its Nu.Q lung test in France, where it hopes to begin commercializing its lung cancer test next year and which it sees as becoming a key market for the company's growth in the near term.
In addition to its lung assay, Volition currently has 14 Nu.Q assays in various stages of development and commercialization. All measure DNA methylation changes at specific regions, such as CpG islands, which may signal early molecular events in tumor evolution. While Batchelor said that lung cancer is the company's current main focus, Volition expects to publish data on its ovarian cancer assay and a new sepsis assay next year.
Volition teamed up with MD Anderson Cancer Center in 2022 to study the role of neutrophil extracellular traps in cancer patients with sepsis.
Liquid biopsies have yet to achieve widespread acceptance as a standalone means of cancer screening, but Batchelor expects studies like the ones in Taiwan to help convince the skeptics. Getting such a test accepted into a large national screening program such as Taiwan's, she said, would signal significant confidence in its worth and help the company expand by licensing its technology out to larger companies with established regional distribution networks.
She said that Volition is currently discussing such licensing deals with "a number" of large diagnostic liquid biopsy companies in East Asia, while continuing to build evidence for its tests through studies such as those being conducted in Taiwan.
"I think [that] continuing to build the clinical evidence and in peer-reviewed journals is the way to go," Batchelor said.